Chronic diseases of the central nervous system (CNS) are a major cause of morbidity and mortality in the developed world. Alzheimer's disease alone affects over five million people in the United States, and is expected to increase to over thirteen million by 2050. The estimated total cost of care in 2012 for people with Alzheimer's disease was over $200 billion and is expected to rise to $1.2 trillion within the next forty years. Moreover, while the proportion of deaths from many other leading causes of mortality in the United States, such as heart disease and stroke, have seen significant decreases over the last decade, the proportion of deaths from Alzheimer's disease has increased 68%. A similar trend, in both high economic cost and a relative lack of progress in treatment, is seen with many other neurodegenerative diseases, including Huntington's disease, Parkinson's disease, and multiple sclerosis.
A major reason for the lack of progress in treating these diseases is due to the presence of the blood-brain barrier (BBB). The BBB is a physical barrier between the CNS parenchyma and vasculature that plays a critical role in maintaining homeostasis within the CNS. Tight junctions exist between endothelial cells that inhibit paracellular diffusion of polar molecules, macromolecules and cells. This forces solute transport into the CNS to occur primarily across individual endothelial cells. Though critically important for maintaining CNS homeostasis, the impermeability of the BBB to most solutes has proven a tremendous obstacle for drug delivery to the CNS. Currently, 98% of small molecule therapeutics and essentially 100% of large-molecule therapeutics, including, monoclonal antibodies, proteins and gene therapies, do not cross the BBB.
Of the several endogenous methods used by solutes to cross the BBB, receptor-mediated transcytosis (RMT) has shown the most promise for use in drug delivery (see, Wiley et al., PNAS, 110(21):8662-667 (2013), which is incorporated by reference herein in its entirety). Although there has been much interest over the past two decades in developing targeted therapeutics for delivery to the brain, there is yet to emerge a viable candidate for clinical investigation.